There is currently an urgent need to identify risk factors that increase vulnerability to develop co-morbid alcoholism and post-traumatic stress disorder (PTSD) in order to devise and implement appropriate prevention and treatment strategies for these disorders. The endocannabinoid system (ECS) modulates anxiety-related and alcohol drinking behaviors and has been identified as a promising target for pharmacotherapies to treat anxiety disorders and alcoholism. For this R21 project, a unique animal model that represents increased genetic risk to develop co-morbid alcoholism and PTSD in humans will be used to study the role of the ECS in influencing fear-related behavior in mice that differ in genetic propensity toward alcohol preference. In Specific Aim 1, male and female mice selectively bred for high (HAP) and low (LAP) alcohol preference will be used to determine whether brain region specific levels of the endocannabinoids, anandamide (AEA) and sn-2 arachidonylglycerol (2-AG), are associated with genetic propensity toward alcohol drinking and fear-related behavior. In Specific Aim 2, it will be determined whether drugs that target the ECS reduce fear-related behavior and whether these effects depend on genetic predisposition toward alcohol preference. The secondary goal of Specific Aim 2 is to determine whether EC brain levels are correlated with observed drug effects on the expression of fear-related behavior. The results of this project will provide exciting new preclinical data on the role of the ECS in modulating fear-related behavior in a unique animal model for co- morbid alcoholism and PTSD. Results from this project may facilitate rapid development of novel pharmacological strategies that target the ECS to treat individuals with co-morbid alcoholism and PTSD. The results may also help identify pharmacotherapy or pharmacoprevention approaches that are particularly effective in people who are at increased genetic risk for both alcoholism and PTSD. PUBLIC HEALTH RELEVANCE: The endocannabinoid system (ECS) modulates anxiety-related and alcohol drinking behaviors and has been identified as a promising target for pharmacotherapies to treat anxiety disorders and alcoholism. The goal of this project is to use a use a unique animal model that represents increased genetic risk to develop co-morbid alcoholism and PTSD in humans to explore the role of the ECS in regulating genetic differences in anxiety- related behavior. The project will also determine whether drugs that target the ECS may represent effective pharmacotherapies to treat individuals with co-morbid alcoholism and PTSD.